1. Field of the Invention
The present invention relates to a method for ameliorating pruritus, and in particular relates to a method of using a phenylbutyric acid or short-chain fatty acid derivative for preventing, treating, or ameliorating pruritus associated with localized or systemic diseases or disorders.
2. Description of the Related Art
As it is known, the cutaneous sensation referred to as pruritus, is characterized by an unpleasant, itchy sensation of the skin which provokes scratching. The scratching is sometimes severe enough to irritate and inflame the skin of afflicted subjects. Pruritus may also be characterized as a uniformed response to a wide variety of physical, chemical, and/or biological stimuli, which may be of an endogenous or exogenous nature that may be associated with specific dermatologic conditions such as allergic reactions to drugs, insect bites and to environmental allergens, or a systemic disease such as thyrotoxicosis, diabetes mellitus, uremia, iron deficiency anemia, delusions of parasitosis, polycythemia rubra vera, cholestasis and Hodgkin's disease. Although usually occurring in the skin, pruritus can also occur in non-cutaneous areas such as mucous membranes. Thus, the cause of pruritus can be multifactorial or due to a single underlying disorder. The pathophysiology of pruritus involves central and peripheral nervous systems as well as multiple cytokine release and molecular mediators.
When the origin of pruritus is in the skin, sensory nerve endings in the dermoepidermal junction are stimulated. The sensation of pruritus is transmitted along dedicated unmyelinated C fibers which are distinct from fibers that transmit pain and touch. The irritated skin will transmit the sensation of pruritus by stimulating local nerves in the spinal cord. From there, the stimulus travels via the lateral spinothalamic tract to the thalamus, and then on to the cerebral cortex, where it causes the sensation of pruritus (Weldon D. Allergy Asthma Proc 28: 153-62, 2007). Gastrin-releasing peptide receptor (GRPR), histamine, substance P, and tumor necrosis factor α (TNF-α) seem to play significant roles in the perception of pruritus (Sun Y G, et al. Nature 448:700-703, 2007). Moreover, for the central neural mechanism where itching is detected, the opioid peptides and the μ receptor have been implicated in provoking the pruritus of cholestasis, which responds to intravenous naloxone (Jones E A, et al. JAMA 268:3359-62, 1992). Meanwhile, serotonin reuptake inhibitors can improve systemic pruritus induced by cholestasis, suggesting that serotonergic pathways are also important in the perception of itching (Mayo M J, et al. Hepatology 45:666-74, 2007).
On the other hand, locally-released substances including histamine, tachykinins, serotonin (5-hydroxytryptamine (5-HT)), interferon (IFN)-gamma, interleukin 2 (IL-2) and IL-4 released from activated macrophage, mast or T cells at the site of pruritoceptive origin have been implicated to cause the symptoms and signs of itching sensation, scratching, swelling, rash, urticaria, and/or scaling (Greaves M W, et al. Lancet 348:938-40, 1996; Inagaki N, et al. Eur J Pharmacol 546:189-96, 2006). Subjects suffering from pruritus induced by a dermatological disorder or systemic disease can possibly worsen the pruritus by excessively scratching the affected area so extensively that the excessive scratching will lead to irritation, inflammation, wound formation and possibly infection. For the peripheral mechanism of pruritus, the role of multiple cytokine release and molecular mediators in the generation of signs and symptoms of pruritus in diseased skin or mucosa has been defined. Histamine-induced pruritus involves H1 receptors (Davies M G, et al. Br J Clin Pharmacol 9:461-65, 1980). Tachykinins including the neuropeptides substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide are found in the cutaneous free-nerve endings of unmyelinated nociceptor neurons which initiate the sensations of pruritis. Intradermal 5-HT can evoke itching and scratching by acting on 5-HT2 and 5-HT3 receptors (Nojima H, et al. J Pharmacol Exp Ther 306:245-52, 2003). These observations have led to the use of a 5-HT2 or 5-HT3 receptor antagonist for treating pruritus (Schworer H, et al. Lancet 341:1277, 1993). IL-2 when given subcutaneously causes intense localized itching in both atopic and normal subjects (Wahlgren C F, et al. Arch Dermatol Res 287:572-80, 1995). Inhibition of IL-2 biosynthesis by immunosuppressive agents such as cyclosporine A relieves the pruritus of atopic dermatitis (Wahlgren C F, et al. Acta Derm Venereol (Stockh) 70:323-29, 1990).
Although antihistamines are widely used for suppression of pruritis, the extent to which suppression is attributable to the side-effect of central sedation rather than local histamine antagonism in the skin is unclear (Krause L, et al. BMJ 287:1199-200, 1983). Many patients report persistent pruritus even with current antihistamines therapies, 5-HT receptor antagonists, and/or immunosuppressive agents, as most are ineffective for chronic pruritus, and only provide short-term relief with side-effects. Pruritus may be quite debilitating for some patients. Thus, there is a continuing need for development of new and improved methods and compositions for preventing, treating, or ameliorating pruritus resulting from a wide variety of causes.
Phenylbutyrate, a short-chain fatty acid, has been approved by the FDA as an orphan drug for inborn error with urea cycle disorder to treat hyperammonemia (Brusilow S W, et al. N Engl J Med 310: 1630-4, 1984). In the human body, phenylbutyrate is metabolized to phenylacetate via β-oxidation. Phenylacetate subsequently undergoes conjugation with glutamine to form phenylacetylglutamine, which serves as a vehicle for waste nitrogen excretion. Recently, phenylbutyrate has also been found to have the ability to inhibit deacetylase, to increase acetylation on histones and non-histone proteins, to remodel chromatin structures and to alter activities of multiple transcriptional factors, resulting in simultaneously, epigenetically modulating many genes and thus, controlling diseases (Marks P A, et al. J Natl Cancer Inst 92: 1210-6, 2000). In preclinical and clinical studies, the gene modulatory effects of phenylbutyrate have exhibited therapeutic potential in many hematologic and solid tumors, inherited genetic disorders such as cystic fibrosis, sickle cell anemia, β-thalassemia, X-linked adrenoleukodystrophy, spinal muscular atrophy, and neurodegenerative disorders, aging, and inflammatory diseases such as autoimmune diseases (Kemp S, et al. Nat Med 4: 1261-8, 1998; et al. Proc Natl Acad Sci USA 102: 11023-8, 2005; Kang H L, et al. Proc Natl Acad Sci USA 99: 838-43, 2002; Blanchard F, et al. Drug Discov Today 10: 197-204, 2005). Moreover, phenylbutyrate can also act as a chemical chaperone to protect normal cells from oxidative stress injury and prevent neurotoxicity (Yam G H, et al. Invest Opthalmol V is Sci 48:1683-90, 2007).